Pulmonary Medication Toolkit: Is yours up to date?

Pulmonary Medication Toolkit: Is yours up to date? Michelle Schymik, PharmD, BCPS Pharmacist for Deaconess Health System Overview Assuming basic knowledge of pulmonary diseases FEEL FREE TO ASK ME ANY QUESTIONS! Focus on pulmonary fibrosis Focus on asthma guidelines update Focus on COPD guideline update Maximizing the use of inhaled medications Objectives List a medication recommended to treat idiopathic pulmonary fibrosis State one change from the GINA guidelines to apply to care of an asthma patient Demonstrate ability to list treatment for a patient with COPD based upon 2017 GOLD guidelines State the medication category and be prepared to counsel a patient for two new inhalers Explain techniques to improve inhaler adherence 1

Having Fun with Technology!! Text MICHELLESCHY461 (this is the text message) to 22333 (this is who or the phone number you text) Focus on Pulmonary Fibrosis 2

Pulmonary Fibrosis Background Idiopathic pulmonary fibrosis 1 Unknown origin + chronic, progressive, fibrotic interstitial lung disease Presents age>45 years (often 6 th or 7 th decade) More men than women Risk factors: Smoking GERD Exposure to metal/wood dust Genetic pre-disposition Age Other types: Familial or Drug-Induced (amiodarone, bleomycin, and nitrofurantoin) Pulmonary Fibrosis Background Idiopathic pulmonary fibrosis 1 Symptoms gradually worse over 6M Cough Wt loss Fever Fatigue Arthralgia/myalgia Symptoms often 1-2 years before diagnosis (often referred to cardiologist for DOE) Overlap with co-morbidities (COPD, PH, GERD, VTE, CAD) Survival often 2.5 years after diagnosis Die from disease (60%), cardiovascular disease, thromboembolic disease Pulmonary Fibrosis and Targets for Medicine Epithelial-fibroblastic disease 1 Damage Irritant exposure (smoke, pollutant, dust, virus, GERD, aspiration) in susceptible host damages alveolar epithelium Attempted Repair Abnormal activation of alveolar epithelial cells releases fibrotic cytokines and growth factors which repair with fibrosis Tumor necrosis factor- (TNF- ), transforming growth factor- (TGF- ), platelet-derived growth factor, insulin-like growth factor-1, endothelin-1 Interferon-γ1b Permanent Fibrosis Result is irreversible destruction of lung tissue 3

Pulmonary Fibrosis Guidelines for Treatment ATS/ERS/JRS/ALAT Clinical Practice Guidelines: Treatment of Idiopathic Pulmonary Fibrosis 1,2 Treat co-morbid conditions GERD, OSA, COPD, CAD Smoking cessation Vaccination influenza and pneumococcal Oxygen Use if hypoxemia at rest of with exercise (PaO 2<55 mmhg or oxygen saturation<88%) Goal=oxygen saturation>90% at rest, with sleep, and with exertion Weight loss if overweight Pulmonary rehab for exercise Pulmonary Fibrosis Guidelines for Treatment STRONG RECOMMENDATION AGAINST USE 2 Anticoagulation with Warfarin 2012 study of 145 pts taking warfarin vs. placebo- stopped early due to lack of benefit and increased mortality (RR=4.73) Imatinib (Gleevec ) Selective tyrosine kinase inhibitor against PDGF receptors Inhibit lung fibroblast-myofibroblast proliferation and inhibit cellular matrix production Study vs. placebo in 119 pts no change in mortality or disease progression, more ADRs Combination prednisone, azathioprine, and N-acetylcysteine Higher mortality (11% vs. 1%), more hospitalizations (29% vs. 8%), more ADRs (31% vs. 9%) Ambrisentan (Letairis ) Selective endothelin receptor (ER-A) antagonist Study vs. placebo in 492 pts - Increased disease progression and mortality (with or without PH) Pulmonary Fibrosis Guidelines for Treatment CONDITIONAL RECOMMENDATION AGAINST USE 2 Sildenafil Phosphodiesterase-5 inhibitor No improvement in 6MWT. Some improvement in dyspnea and QOL Macitentan and Bosentan Dual endothelin receptor (ER-A and ER-B) antagonist Bosentan vs. placebo in 2 studies no effect on mortality or symptoms Macitentan vs. placebo no effect on mortality or disease progression N-acetylcysteine alone Two studies (Japanese study and arm of triple therapy) no change in FVC decline CONDITIONAL RECOMMENDATION FOR USE Antiacid therapy for pts with GERD (found in 90% of IPF pts) to prevent aspiration 4

Pulmonary Fibrosis Guidelines for Treatment CONDITIONAL RECOMMENDATION FOR USE 2 Nintedanib (Ofev ) approved 10/14 Tyrosine kinase inhibitor (non-selectively targets vascular endothelial growth factor, fibroblast growth factor, and PDGF receptors) 12-month trial (150mg BID) - lower annual rate of decline in FVC and fewer exacerbations vs. placebo INPULSIS-1 and INPULSIS-2: Two 52-week trials Stat sig improvement in FVC (>10% improvement) vs. placebo No difference in mortality or exacerbations More adverse events Pts in studies had mild-moderate IPF $96,000 per year Outcomes: *Slow progression *Decrease exacerbation? Pulmonary Fibrosis Guidelines for Treatment Nintedanib (Ofev ) 3 Dosing: 150mg po BID (12h apart) with food Decrease dose to 100mg BID for mild hepatic impairment; Avoid moderate/severe Do not chew or crush Drug Interactions P-gp and CYP3A4 inhibitors may increase effect Smoking decreased effect Precautions/Side Effects: Elevated liver enzymes (14%) baseline and periodic AST, ALT, bili Check pregnancy test at baseline (can cause fetal harm) Arterial thrombotic effects (avoid if risk of CV disease) Risk of increased bleeding Nausea (24%), vomiting (12%), diarrhea (62%), abdominal pain(15%), GI perforation Diarrhea lead to: *Dose reduction in 11% *Discontinuation in 5% Nausea lead to: *Discontinuation in 2% Vomiting lead to: *Discontinuation in 1% Pulmonary Fibrosis Guidelines for Treatment CONDITIONAL RECOMMENDATION FOR USE 2 Pirfenidone (Esbriet ) approved 10/14 Anti-fibrotic - combined anti-inflammatory, antioxidant, and anti-fibrotic effects Inhibits Tumor necrosis factor- (TNF- ) and transforming growth factor- (TGF- ) Initial study (stopped early) fewer exacerbations, less O 2 desaturation during 6MWT, and less decrease in FVC CAPACITY 72-week pooled data 2403mg/day showed sig less FVC decline. More side effects Individual trials one showed benefit and other showed no benefit in FVC $94,000 per year ASCEND (more strict inclusion) less decrease in FVC at 52 weeks, improved 6MWT, improved progression free survival. More side effects Outcomes: Pts in studies had mild-moderate IPF *Slow progression 5

Pulmonary Fibrosis Guidelines for Treatment Pirfenidone (Esbriet ) 4 Dosing: 801mg po TID (with food) Dose is titrated up over 14 days Decrease dose for hepatic or renal insufficiency Precautions/Side Effects: Elevated liver enzymes baseline and periodic AST, ALT, bilirubin Photosensitivity GI disorders nausea, vomiting, dyspepsia, GERD, abdominal pain Rash (rare to cause discontinuation) Drug Interactions Moderate (Cipro) and Strong (fluvoxamine) CYP1A2 increase Pirfenidone Smoking decreases effect Pulmonary Fibrosis Guidelines for Treatment Lung transplant IPF now replaces COPD as reason for transplant 2 Refer to transplant center at diagnosis 5-year survival after lung transplant for IPF is 50-56% No difference in survival single vs. double-lung transplant higher No recommendation in guidelines Treatment of acute exacerbation (AE-IPF) 2 Rule out infectious causes Oxygen + Methylprednisolone 2mg/kg/day IV x 2 weeks then taper 6

Pulmonary Fibrosis Guidelines for Treatment 5 Pulmonary Fibrosis Future Medications 6 Compound Mechanism/Target Role of Attacking Target PRM-151 Recombinant human protein called Pentraxin-2 Active at site of tissue damage IW001 Prevents immune response to activated Type V collagen Presents lung damage TD139 Inhibitor of the galactoside Prevents fibrosis development BMS-986020 Lysophosphatidic acid-1 receptor antagonist Blocks development of fibrosis FG-301 Monoclonal antibody against connective tissue growth factor Prevents tissue remodeling and fibrosis Lebrikizumab Monoclonal antibody against interleukin (IL)-13 Fixes high level found in IPF Tralokinumab Human IL-13-neutralizing monoclonal antibody Fixes high level found in rapidly progressing IPF SAR156597 Bispecific antibody that neutralizes IL-4 and IL-13 Prevent fibrosis Simtuzumab Monoclonal antibody against lysyl oxidase-like 2 (LOXL2) Prevents collagen crosslink STX-100 Monoclonal antibody against the integrin avb6 Prevent fibrogenesis Focus on Asthma guidelines update 7

Asthma Guidelines available National Asthma Education and Prevention Program (NAEPP) 7 Last updated 2007 Veteran s Administration/Department of Defense (VA/DoD) 8 Last updated 2009 Global Initiative for Asthma (GINA) 9 Last updated 2017 Not a guideline, but a practical approach Asthma Classification Based upon Guidelines 7-9 NAEPP & VA/DoD = Symptom-Based GINA = Control-Based Mild asthma: Well-controlled with PRN SABA or low dose ICS Moderate asthma: Well-controlled with low-dose ICS/LABA Severe asthma: Requires moderate or high dose ICS/LABA ± add-on or Remains uncontrolled despite this treatment Asthma - Focus in GINA 2017 9 Independent risk factors for exacerbations include: Ever intubated for asthma Uncontrolled asthma symptoms Having 1 exacerbation in last 12 months Low FEV 1 (measure at start of treatment, at 3-6M to assess personal best, and periodically) Incorrect inhaler technique and/or poor adherence Smoking Elevated FeNO (fractional exhaled nitric oxide) in adults with allergic asthma Obesity, pregnancy, blood eosinophilia 8

Asthma - Focus in GINA 2017 9 Focus on severe vs. uncontrolled Uncontrolled (more persistent symptoms/exacerbations, more easily controlled) Evaluate for Poor inhaler technique (require demonstration), Poor medication adherence (address cost, complexity, understanding) Co-morbidities Environmental factors Asthma control should be assessed at every interaction (even refills) Asthma - Focus in GINA 2017 9 Asthma-COPD Overlap Removed the word syndrome since not one disease Common, but not often seen in clinical trials Conflicting evidence makes treatment difficult Asthma never use LABA without ICS COPD start treatment with LABA and/or LAMA (without ICS) Repeat lung function test at least every 1-2 years Children with persistent asthma Reduced growth in lung function and may have accelerated decline as adults Asthma - Focus in GINA 2017 9 FeNO Not useful for diagnosis of asthma Elevated FeNO in allergic patient is risk factor for exacerbations Single measure of FeNo interpret with caution Not able to use to decide against inhaled steroids (not enough trial information) Other items reviewed Vitamin D no proof that improves asthma control Nasal steroids does help nasal symptoms, but does not help asthma control 9

Asthma - Focus in GINA 2017 9 Effect of steroids on growth of children Check height yearly (consider referral if growth delay) Poorly control asthma can affect growth In 1 st 1-2 years of inhaled steroids, growth velocity may be slowed Educate parents Possible effects on growth and importance of physical activity Impact on growth velocity is not cumulative or progressive Different in adult height may only be 0.7% Infant cough (chronic and no cold) associated with asthma No prevention strategy in utero found to prevent asthma Stepwise approach to control asthma symptoms and reduce risk Stepwise approach to control asthma symptoms and reduce risk 10

Stepwise approach to control asthma symptoms and reduce risk Stepwise approach to control asthma symptoms and reduce risk 11

Focus on COPD guidelines update COPD 2017 GOLD Guideline Changes 10 Definition of COPD COPD is a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases. Removed usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung COPD may be punctuated by acute worsening of respiratory symptoms, called exacerbations. Dyspnea, cough and/or sputum production are the most frequent symptoms; symptoms are commonly under-reported by patients. No longer use chronic bronchitis or emphysema COPD Guideline Changes Assessment Less emphasis on spirometry Severity based upon symptoms and not spirometry Symptoms and exacerbations correlate more with functional limitations and QOL 12

COPD Guideline Changes 10 Smoking Cessation Uses U.S. Preventive Services Task Force s guidelines for smoking cessation: Offer Nicotine replacement Cessation counseling Pharmacotherapy (varenicline, bupropion, or nortriptyline) Efficacy and safety of e-cigarettes is unclear COPD Guideline Changes 10 Oxygen - Not recommended for stable COPD patients without severe resting hypoxemia Did not improve QOL or outcomes Pharmacotherapy SABA/SAMA combination - stronger recommendation because superior to SABA or SAMA alone in improving symptoms and FEV 1 LABA/LAMA combination preferred over LABA/ICS Fewer exacerbations (vs. monotherapy or LABA/ICS) More improvement in FEV 1 (vs. monotherapy) ICS associated with pneumonia Elevated blood eosinophils LABA/ICS had more effect on decreasing exacerbations than LABA with high eosinophil counts Escalation and De-escalation plan COPD Guideline Changes 10 13

COPD Guideline Changes 10 COPD Guideline Changes 10 COPD Guideline Changes 10 Improved lung function, symptoms, and exacerbation 14

Keeping up with inhaled medications Inhaler Education Tips Only ½ to 1/3 of patients use inhalers correctly SABA separate puffs by 3 minutes Priming inhaler required for MDI (HFA or soft-mist) Initial use and if not used for specific number of days HFA closed-mouth technique recommended Dry Powder Breath out away from inhaler Require quick and deep inhalation Hold flat once activate the dose Handihaler and Neohaler must puncture capsule with piercing button Inhalers are supposed to be cleaned 15

Inhaler Education Tips Common Mistakes Not shaking inhalers 2 puffs at the same time (one breath) Poor technique (timing, inspiration, covering holes) Tilting a dry powder inhaler Not rinsing after steroid inhaler Not using scheduled doses when they should be scheduled Interventions known to improve adherence Shared decision making Comprehensive asthma education with home visits Inhaler reminders for missed doses Reviewing patient s refill records Information from GINA 2017 9 Choose Choose an appropriate device before prescribing. Consider medication options, arthritis, patient skills and cost. For ICS by pmdi, prescribe a spacer Avoid multiple different inhaler types if possible Check Check technique at every opportunity Can you show me how you use your inhaler at present? Identify errors with a device-specific checklist Correct Give a physical demonstration to show how to use the inhaler correctly Check again (up to 2-3 times) Re-check inhaler technique frequently, as errors often recur within 4-6 weeks Confirm Can you demonstrate correct technique for the inhalers you prescribe? Brief inhaler technique training improves asthma control Short-Acting Bronchodilators (SABA and SAMA) Drug Mechanism Dosing Frequency Delivery Type Wholesale Cost for 30-day supply Albuterol SABA (ProAir HFA, Proventil HFA, Ventolin HFA) 2 puffs QID and/or PRN MDI Neb Inhaler $50-60 Levalbuterol (Xopenex HFA) SABA 2 puffs QID and/or PRN MDI Neb Inhaler $70 Ipratropium (Atrovent HFA) SAMA 2 puffs QID and/or PRN Inhaler Neb Inhaler $285 16

Long-Acting Beta-Agonists (LABA) Drug Mechanism Dosing Frequency Delivery Type Wholesale Cost for 30-day supply Formoterol (Foradil Aerolizer) Indacaterol (Arcapta Neohaler) Olodaterol (Striverdi Respimat) Salmeterol (Serevent Diskus) LABA BID Inhaler $240 LABA Daily Neohaler DPI capsule $213 LABA Daily Respimat $155 LABA BID Diskus - DPI $322 Long-acting Muscarinic Antagonists (LAMA) Drug Mechanism Dosing Frequency Aclidinium (Tudorza Pressair) Glycopyrrolate (Seebri Neohaler) Tiotropium (Spiriva HandiHaler) (Spiriva Respimat) Umeclidinium (Incruse Ellipta) Delivery Type LAMA BID Pressair - DPI $242 LAMA BID Neohaler DPI capsule $297 LAMA Daily Inhaler Handihaler DPI capsule Respimat - Wholesale Cost for 30-day supply $315 LAMA Daily Ellipta - DPI $252 LAMA superior to LABA to prevent exacerbation of COPD (preferred if >2 exacerbations or hospital x 1 in last year) Beta-Agonist + Anticholinergic Drug Mechanism Dosing Delivery Type Frequency Albuterol/Ipratropium (Combivent Respimat) Formoterol/Glycopyrrolate (Bevespi Aerosphere) Indacaterol/Glycopyrrolate (Utibron Neohaler) Olodaterol/Tiotropium (Stiolto Respimat) Vilanterol/Umeclidinium (Anoro Ellipta) SABA + SAMA LABA + LAMA LABA + LAMA LABA + LAMA LABA + LAMA QID Respimat Neb BID MDI $334 BID Neohaler DPI capsule $297 Daily Respimat $315 Daily Ellipta - DPI $315 Wholesale Cost for 30-day supply Respimat $300 17

Inhaled Corticosteroids (ICS) Drug Mechanism Dosing Frequency Delivery Type Wholesale Cost for 30-day supply Beclomethasone (Qvar) Budesonide (Pulmicort Flexhaler Ciclesonide (Alvesco) Flunisolide (Aerospan) Fluticasone (Arnuity Ellipta) (Flovent HFA or Flovent Diskus) Mometasone (Asmanex Twisthaler) ICS BID MDI $150 ICS BID Flexhaler = DPI $170 ICS BID MDI $190 ICS BID MDI $250 ICS Daily or BID HFA - MDI $180-220 Diskus/Elllipta DPI ICS BID Twisthaler - DPI $150 Beta-Agonists+Inhaled Corticosteroids (LABA/ICS) Drug Mechanism Dosing Frequency Formoterol/Budesonide (Symbicort) Salmeterol/Fluticasone (Advair Diskus, Advair HFA) (AirDuo Respiclick)-COPD only Formoterol/Mometasone (Dulera)-asthma only Vilanterol/Fluticasone (Breo Ellipta) Delivery Type LABA + ICS BID MDI $197 LABA + ICS BID Diskus-DPI HFA MDI AirDuo - Respiclick LABA + ICS BID MDI $240 LABA + ICS Daily Ellipta - DPI $297 Wholesale Cost for 30-day supply Advair $440 AirDuo $285 Generic $90 18

References 1. Godfrey AMK, Byrd RP, Ouellette DR, et al. Idiopathic pulmonary fibrosis. http://emedicine.medscape.com/article/301226-overview. Accessed 17 August 2017. 2. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis: Executive Summary An Update of the 2011 Clinical Practice Guideline. https://www.thoracic.org/statements/resources/interstitial-lung-disease/ipf-exec-sum.pdf. Accessed 24 May 2017. 3. Ofev [Prescribing Information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2017. 4. Esbriet [Prescribing Information]. South San Francisco, CA: Genentech; 2017. 5. Santhosh L. 2015 ATS guidelines on treatment of IPF released. http://pulmccm.org/main/2015/interstitial-lung-disease-review/2015-ats-guidelines-ontreatment-of-ipf-released/. Accessed 17 August 2017. 6. Spagnolo P, Bonella F, Vasakova M, et al. Current and Future Therapies for Idiopathic Pulmonary Fibrosis. https://link.springer.com/article/10.1007/s41030-015- 0009-4. Accessed 17 August 2017. 7. National Asthma Education and Prevention Program's Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Full Report 2007. J Allergy Clin Immunol. 2007;120(5):S94-138 8. Management of Asthma Working Group: VA/DoD clinical practice guidelines for management of asthma in children and adults. Washington (DC): Department of Veterans Affairs, Department of Defense. 2009 9. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2017. Available from: www.ginasthma.org. Accessed 7 August 2017. 10. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 at http://goldcopd.org. Accessed 17 Augusst 2017. 11. FDA Approved Drugs for Pulmonary/Respiratory Diseases. https://www.centerwatch.com/drug-information/fda-approved-drugs/therapeuticarea/18/pulmonary-respiratory-diseases. Accessed 24 May 2017. 12. PL Detail-Document, Inhalers for COPD. Pharmacist s Letter/Prescriber s Letter. January 2015. 13. Clinical Resource, Correct Use of Inhalers. Pharmacist s Letter/Prescriber s Letter. January 2017. Pulmonary Medication Toolkit: Is yours up to date? Michelle Schymik, PharmD, BCPS Pharmacist for Deaconess Health System 19